Compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier

ABSTRACT

This invention relates generally to compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-In-Part of U.S. patent applicationSer. No. 13/165,642, filed on Jun. 21, 2011, which application claimspriority under 35 U.S.C. §119(e) to U.S. Provisional Patent ApplicationSer. No. 61/357,485, filed on Jun. 22, 2010, and to U.S. ProvisionalPatent Application Ser. No. 61/419,773, filed on Dec. 3, 2010, each ofwhich applications are incorporated by reference herein in theirentirety.

FIELD OF THE INVENTION

This invention relates generally to compositions comprising noribogaineand an excipient to facilitate transport across the blood brain barrier.

STATE OF THE ART

Noribogaine is a well known derivative of ibogaine and is sometimesreferred to as 12-hydroxyibogaine. It is a metabolite of ibogaine. U.S.Pat. No. 2,813,873 claims noribogaine albeit as “12-O-demethylibogaine”while providing an incorrect structural formula for ibogaine. Thestructure of noribogaine has now been thoroughly evaluated and is foundto combine the features of tyrptamine, tetrahydrohavaine andindolazepines. Noribogaine can be depicted by the following Formula:

Noribogaine and its pharmaceutically acceptable salts have recentlyreceived significant attention as non-addictive alkaloids useful intreating drug dependency (U.S. Pat. No. 6,348,456) and as a potentanalgesic (U.S. Pat. No. 7,220,737).

Noribogaine is typically administered orally or intravenously andbecomes systemically available to the treated patient. While noribogaineallosterically binds tightly to the μ and κ receptors, the systemiccirculation of noribogaine increases the likelihood of undesirable sideeffects while the availability of noribogaine is limited by theefficiency of its passage across the blood brain barrier.

Accordingly, there is a need to reduce the systemic circulation ofnoribogaine while maintaining or increasing its concentration in thebrain particularly at the μ and κ receptors.

SUMMARY OF THE INVENTION

This invention relates to increased cranial delivery of noribogaine byuse of a pharmaceutically acceptable excipient to enhance blood brainbarrier penetration. It is contemplated that the excipient cooperativelyincreases the concentration of noribogaine in the brain of the treatedpatient thereby reducing the systemic concentration of noribogaine inthe remainder of the patient's body. While not all drugs reactcooperatively with blood brain barrier excipients, it is contemplatedthat noribogaine will show a significant increase in cranialconcentration when used in conjunction with such an excipient. It isfurther contemplated that in view of such targeted delivery, the amountof noribogaine required to effect therapy will be reduced.

Accordingly, in one of its composition aspects, this invention isdirected to a pharmaceutical composition comprising a therapeuticallyeffective amount of noribogaine, or a derivative or pharmaceuticallyacceptable salt thereof, and an effective amount of a pharmaceuticallyacceptable excipient to enhance the blood brain barrier penetration ofnoribogaine.

In some embodiments, the excipient which enhances the blood brainbarrier penetration of noribogaine is a biocompatible dehydratingsaccharide such as mannitol.

In some embodiments, at least a portion of the mannitol or otherdehydrating saccharide is bound to the noribogaine via a biocompatible,cleavable linking group. It is contemplated that such compounds willreduce the concentration of the saccharide necessary to enhance theblood brain barrier penetration of noribogaine. In one such embodiment,there is provided a compound of Formula I:

wherein

-   is a single or double bond;-   R is hydrogen, alkyl, —C(O)-alkyl, or the group -L-S where L is a    covalent bond or is a biocompatible, cleavable linking group and S    is a dehydrating saccharide or oligosaccharide;-   R¹ is hydrogen or the group -L-S where L is a covalent bond or is a    biocompatible, cleavable linking group and S is a dehydrating    saccharide or oligosaccharide; provided that at least one of R and    R¹ is -L-S;-   or a pharmaceutically acceptable salt thereof.

In another of its composition aspects, there is provided a compound ofFormula I or its pharmaceutically acceptable salt.

In some embodiments, R is hydrogen and R¹ is -L-S. In some embodiments,R is —C(O)-alkyl and R¹ is -L-S. In some embodiments, R is -L-S and R¹is hydrogen. In some embodiments, both R and R¹ are -L-S.

In another of its composition aspects, this invention is directed to apharmaceutical composition comprising a pharmaceutically acceptableexcipient and a therapeutically acceptable amount of a compound ofFormula I above.

In some embodiments, R is hydrogen and R¹ is -L-S. In some embodiments,R is -L-S and R¹ is hydrogen. In some embodiments, R is —C(O)-alkyl andR¹ is -L-S. In some embodiments, both R and R¹ are -L-S. In someembodiments, the pharmaceutically acceptable excipient comprisesmannitol.

In one of its method aspects, there is provided a method for treatingpain in a patient which method comprises administering to said patient apharmaceutical composition comprising a therapeutically effective amountof noribogaine or a pharmaceutically acceptable salt thereof and aneffective amount of a pharmaceutically acceptable excipient to enhancethe blood brain barrier penetration of noribogaine.

In another of its method aspects, there is provided a method fortreating addiction in a patient which method comprises administering tosaid patient a pharmaceutical composition comprising a therapeuticallyeffective amount of noribogaine or a pharmaceutically acceptable saltthereof and an effective amount of a pharmaceutically acceptableexcipient to enhance the blood brain barrier penetration of noribogaine.

In one of its method aspects, there is provided a method for treatingpain in a patient which method comprises administering to said patient atherapeutically effective amount of a compound of Formula I or apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula I and a pharmaceutically acceptable excipient.

In another of its method aspects, there is provided a method fortreating addiction in a patient which method comprises administering tosaid patient a therapeutically effective amount of a compound of FormulaI or a pharmaceutical composition comprising a therapeutically effectiveamount of a compound of Formula I and a pharmaceutically acceptableexcipient.

DETAILED DESCRIPTION

This invention is directed to compositions comprising noribogaine, or aderivative or pharmaceutically acceptable salt thereof, and an excipientto facilitate transport across the blood brain barrier.

It is to be understood that this invention is not limited to particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present invention will be limited onlyby the appended claims.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “anexcipient” includes a plurality of excipients.

1. DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. As used herein the followingterms have the following meanings.

As used herein, the term “comprising” or “comprises” is intended to meanthat the compositions and methods include the recited elements, but notexcluding others. “Consisting essentially of” when used to definecompositions and methods, shall mean excluding other elements of anyessential significance to the combination for the stated purpose. Thus,a composition consisting essentially of the elements as defined hereinwould not exclude other materials or steps that do not materially affectthe basic and novel characteristic(s) of the claimed invention.“Consisting of” shall mean excluding more than trace elements of otheringredients and substantial method steps. Embodiments defined by each ofthese transition terms are within the scope of this invention.

The term “about” when used before a numerical designation, e.g.,temperature, time, amount, and concentration, including range, indicatesapproximations which may vary by (+) or (−) 10%, 5% or 1%.

As stated above, the invention is directed to compositions comprisingnoribogaine, or a derivative or pharmaceutically acceptable saltthereof, and an excipient to facilitate transport across the blood brainbarrier.

As used herein, the term “noribogaine” refers to the compound:

as well as its pharmaceutically acceptable salts thereof.Conventionally, noribogaine is prepared by demethylation of naturallyoccurring ibogaine:

which is isolated from Tabernanthe iboga, a shrub of West Africa.Demethylation may be accomplished by conventional techniques such as byreaction with boron tribromide/methylene chloride at room temperaturefollowed by conventional purification. (See, for example, Huffman, etal., J. Org. Chem. 50:1460 (1985)). Methods for the synthesis andpurification of noribogaine are disclosed in U.S. patent applicationSer. No. 13/104,406, entitled Methods and Compositions for Preparing andPurifying Noribogaine, filed on May 10, 2011, which is herebyincorporated by reference in its entirety. This invention is not limitedto any particular chemical form of noribogaine and the drug may be givento patients either as a free base or as a pharmaceutically acceptableaddition salt.

As used herein, the terms “blood-brain barrier” or “BBB” refer to thebarrier between the peripheral circulation and the brain and spinal cordwhich is formed by tight junctions within the brain capillaryendothelial plasma membranes, creating an extremely tight barrier thatrestricts the transport of molecules into the brain. The blood-brainbarrier within the brain, the blood-spinal cord barrier within thespinal cord, and the blood-retinal barrier within the retina, arecontiguous capillary barriers within the central nervous system (CNS),and are collectively referred to herein as the blood-brain barrier orBBB.

As used herein, the term “derivative” refers to derivatives ofnoribogaine that maintain or enhance the activity of noribogaine, or aremetabolized within the patient to form noribogaine. Suitable derivativesare disclosed in U.S. patent application Ser. No. 13/104,410, entitledSubstituted Noribogaine, filed on May 10, 2011, which is herebyincorporated by reference in its entirety.

As used herein, the term “pharmaceutically acceptable excipient toenhance blood brain barrier penetration” refers to a substance that iscapable of disrupting or penetrating the blood brain barrier. In oneembodiment, the disruption is a transient disruption. The amount ofpharmaceutically acceptable excipient administered with the noribogaineor derivative thereof is the amount effective to disrupt the blood brainbarrier and allow noribogaine to enter the brain.

As used herein, the term “biocompatible dehydrating saccharide” refersto a saccharide or derivative thereof, having at least 6 carbon atoms(which may be linear, branched or cyclic) with an oxygen, nitrogen orsulfur atom bonded to each carbon atom. The term “biocompatibledehydrating oligosaccharides” includes oligosaccharides containing fromabout 2-9 monosaccharide units. Specific monosaccharides include C₅ andabove (preferably C₅-C₈) saccharides such as ethritol, zylitol,galactose, lactose, xylose, dulcitol, myo-insoitol, fructose, mannitol,sorbitol, glucose, arabinose, arabinose, celloboise, maltose, raffinose,rhamnose, melibiose, ribose, adonitol, arabitol, arabitol, fucose,lyxose, lyxose, lyxose, glucosamine, mannosamine, and galactosamine; di-and trisaccharides include saccharides having two or threemonosaccharide units.

As used herein, the term “mannitol” refers to(2R,3R,4R,5R)-hexane-1,2,3,4,5,6-hexyl

Mannitol is a polyol and has been used as an osmotic diuretic agent anda weak renal vasodilator. It was originally isolated from the secretionsof the flowering ash, called manna after their resemblance to theBiblical food, and is also be referred to as mannite and manna sugar.Mannitol and derivatives thereof are readily available from commercialsources or can be synthesized using procedures known in the art. In itspyranose or condensed form, mannitol becomes a 6 membered ringsaccharide (sugar) of the formula:

and is referred to as α-D-mannopyranose. As used herein, all saccharidesare meant to include both their open forms as well as their pyranoseforms including their naturally occurring D or L forms of thesaccharide.

As used herein, the term “pharmaceutically acceptable salt” refers tosalts derived from organic or inorganic acids. Examples of such acidsinclude, without limitation, hydrochloric acid, hydrobromic acid,phosphoric acid, sulfuric acid, methane sulfonic acid, phosphorous acid,nitric acid, perchloric acid, acetic acid, tartaric acid, lactic acid,succinic acid, citric acid, malic acid, maleic acid, aconitic acid,salicylic acid, thalic acid, embonic acid, enanthic acid, and the like.

As used herein, the term “biocompatible, cleavable linking group” refersto a linking group that can be attached to noribogaine at any possibleposition such that the linker is biocompatible (i.e. does not produceundesired side effects or have an intolerable toxicity), is readilycleaved in the body (preferably in the brain), and does not inhibit oralter the desired physiological effect of noribogaine. Specifically, thelinking group should be sufficiently stable in the circulatory system(serum or blood), but is cleaved to release the noribogaine upon entryinto the brain. Suitable biocompatible, cleavable linking groupscomprise from 1 to 20 atoms selected from carbon, nitrogen, oxygen,sulfur, and phosphorus, and are, in general, susceptible to cleavageconditions or agents in the brain (i.e. pH, redox potential or thepresence of degradative molecules such as enzymes). The biocompatible,cleavable linking group can be an ester-based cleavable linking group(—C(O)O— or —OC(O)—), an amide-based cleavable linking group (—C(O)NR—or —NRC(O)—), or a phosphate-based cleavable linking group(—P(O)(OR)—O—, —O—P(S)(OR)—O—, —O—P(S)(SR)—O—, —S—P(O)(OR)—O—,—O—P(O)(OR)—S—, —S—P(O)(OR)—S—, —O—P(S)(OR)—S—, —S—P(S)(OR)—O—,—O—P(O)(R)—O—, —O—P(S)(R)—O—, —S—P(O)(R)—O—, —S—P(S)(R)—O—,—S—P(O)(R)—S—, or —O—P(S)(R)—S—) where R can be hydrogen or alkyl.

As used herein, the term “alkyl” refers to a monovalent saturatedaliphatic hydrocarbyl group having from 1 to 12 carbon atoms, or 1 to 6carbon atoms. The term “Cx” means an alkyl group with x carbon atoms. Insome embodiments, one or more of the hydrogen atoms of the alkyl groupcan be replaced with a functional group such as —OH, —NH₂, —SH, and thelike. This term includes, by way of example, linear and branchedhydrocarbyl groups such as methyl (CH₃—), ethyl (CH₃CH₂—), n-propyl(CH₃CH₂CH₂—), isopropyl ((CH₃)₂CH—), n-butyl (CH₃CH₂CH₂CH₂—), isobutyl((CH₃)₂CHCH₂—), sec-butyl ((CH₃)(CH₃CH₂)CH—), t-butyl ((CH₃)₃C—),n-pentyl (CH₃CH₂CH₂CH₂CH₂—), and neopentyl ((CH₃)₃CCH₂—). As usedherein, the term “alkoxy” refers to O-alkyl.

As used herein, the term “therapeutically acceptable amount” refers tothe amount of a composition of this invention that is sufficient toeffect treatment, as defined herein, when administered to a subject inneed of such treatment. The therapeutically effective amount will varydepending upon the subject and condition being treated, the weight andage of the subject, the severity of the condition, the particularcomposition or excipient chosen, the dosing regimen to be followed,timing of administration, the manner of administration and the like, allof which can be determined readily by one of ordinary skill in the art.

As used herein, the term “treatment” or “treating” means any treatmentof a disease or condition in a patient, including:

-   -   preventing or protecting against the disease or condition, that        is, causing the clinical symptoms not to develop, for example,        in a subject at risk of suffering from such a disease or        condition, thereby substantially averting onset of the disease        or condition;    -   inhibiting the disease or condition, that is, arresting or        suppressing the development of clinical symptoms; and/or    -   relieving the disease or condition that is, causing the        regression of clinical symptoms.

As used herein, the term “pain” refers to all types of pain, includingneuropathic and nociceptive pain. It is also contemplated that thecompositions disclosed herein can be used to treat other types of painsuch as phantom pain which is the sensation of pain from a limb or organthat has been lost or from which a person no longer receives physicalsignals, and is an experience almost universally reported by amputeesand quadriplegics.

As used herein, the term “addiction” refers to a persistent behavioralpattern marked by physical and/or psychological dependency to asubstance, particularly drugs such as narcotics, stimulants, andsedatives, including but not limited to heroin, cocaine, alcohol,nicotine, caffeine, amphetamine, desoxyephedrine, methadone andcombinations thereof. As used herein, the “treatment of addiction in apatient” refers to reducing the withdrawal symptoms associated with drugdependency as well as alleviating drug cravings in addicts. Suchsymptoms include nausea, vomiting, anxiety, abdominal cramps, musclepain, chills and headache.

As used herein, the term “patient” refers to mammals and includes humansand non-human mammals.

Excipients for Penetrating the Blood Brain Barrier

The blood brain barrier (BBB) functions to protect the brain fromexposure to toxins, both endogenous and exogenous. However, thisprotection severely limits the therapeutic ability of many of drugs byinhibiting their crossing from the circulatory system into the brain. Inorder for a drug to enter the brain and cross the BBB, molecules musteither passively diffuse or be actively transported across the BBB.Water soluble or polar compounds must be actively transported across theBBB, whereas it has been shown that drugs which passively diffuse intothe brain have fewer hydrogen bond donors, fewer positive charges,greater lipophilicity, lower polar surfaces, reduced flexibility, andare small (i.e. less than 400-500 Da) (see Pardridge MolecularInterventions, 2003, 3:2, 90-105, Deeken, et al. Clin Cancer Res, 2007,13:6, 1663-1674 and references cited therein). However, in someinstances, a pharmaceutically acceptable excipient can be used toenhance blood brain barrier penetration (see Pan, et al. Acta PharmacolSin, 2000, 21:7, 613-616). This invention is relates to increasedcranial delivery of noribogaine by use of a pharmaceutically acceptableexcipient to enhance blood brain barrier penetration.

It is contemplated that the pharmaceutically acceptable excipientcooperatively increases the concentration of noribogaine in the brain ofthe treated patient thereby reducing the systemic concentration ofnoribogaine in the remainder of the patient's body. While not all drugsreact cooperatively with blood brain barrier excipients, it iscontemplated that noribogaine will show a significant increase incranial concentration when used in conjunction with such an excipient.It is further contemplated that in view of such targeted delivery, theamount of noribogaine required to effect therapy will be reduced. Inaddition, it is contemplated that the compositions disclosed hereinprovide for an increased serum half-life when compared to noribogainealone.

In one embodiment, the present invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount ofnoribogaine, or a derivative or pharmaceutically acceptable saltthereof, and an effective amount of a pharmaceutically acceptableexcipient to enhance the blood brain barrier penetration of noribogaine.Methods for the synthesis and purification of noribogaine to be used inthe compositions of the present invention are disclosed in U.S. patentapplication Ser. No. 13/104,406, entitled Methods and Compositions forPreparing and Purifying Noribogaine, filed on May 10, 2011, which ishereby incorporated by reference in its entirety. Suitable derivativesare disclosed in U.S. patent application Ser. No. 13/104,410, entitledSubstituted Noribogaine, filed on May 10, 2011, which is herebyincorporated by reference in its entirety.

In the present invention, the composition comprises an excipient capableof transiently disrupting the BBB and allowing noribogaine to penetratethe blood brain barrier. The disrupting effects of such excipientsshould not produce functional neurological deficits, long-term brainedema, or brain pathology. In one embodiment, the composition comprisesa hypertonic solution which transiently disrupts the BBB by causing thecells which make up the BBB to dehydrate and shrink. This dehydrationand shrinkage disrupts the BBB by compromising the tight junctionsbetween the cells and thus forming passages into the brain.

In a certain embodiment, the excipient which enhances the blood brainbarrier penetration of noribogaine is a biocompatible dehydratingsaccharide, such as mannitol. Suitable concentrations are known to thoseof skill in the art or can be readily determined using known methods. Inone embodiment, it is contemplated that the concentration of mannitol inthe composition is about 1.1 M. In another embodiment, mannitol isadministered at a concentration of from about 0.1 mol/L to about 10mol/L, or alternatively, at a concentration of from about 0.5 mol/L toabout 5 mol/L.

Other excipients which are contemplated to be capable of enhancingpenetration of noribogaine across the blood brain barrier includesaccharides or saccharide derivatives (i.e. amino saccharides),bradykinin B2 receptor agonists (i.e. Cereport®), small fat-solublemolecules (i.e. ethanol or ethanol derivatives), naturally occurring orsynthetic amino acids, choline, and purine bases or nucleosides orderivatives thereof. Other blood brain barrier excipients can be usedthat are known to those of ordinary skill in the art. Exemplarysaccharides which can be used in the compositions and methods disclosedherein include, any one or more of ethritol, zylitol, galactose,lactose, xylose, dulcitol, myo-insoitol, fructose, mannitol, sorbitol,glucose, arabinose, arabinose, celloboise, maltose, raffinose, rhamnose,melibiose, ribose, adonitol, arabitol, arabitol, fucose, lyxose, lyxose,lyxose, glucosamine, mannosamine, and galactosamine. Excipients may alsocomprise one or more naturally occurring (endogenous or exogenous) orsynthetic amino acid or derivative thereof, such as arginine,asparagine, aspartic acid, cysteine, glutamic acid, glycine, histidine,leucine, methionine, phenylalanine, proline, serine, threonine,glutamine, lysine, tryptophan, tyrosine, valine, taurine and L-dopa (anaturally occurring amino acid, dihydroxyphenyalanine, found in broadbeans).

Biocompatible, Cleavable Linking Groups

In one embodiment of the present invention, at least a portion of theexcipient capable of enhancing blood brain barrier penetration is boundto the noribogaine via a covalent bond or a biocompatible, cleavablelinking group. The covalent bond or linking group can be attached to thenoribogaine at any possible position such the bond or biocompatiblelinker is readily cleaved in the body and does not inhibit or alter thedesired physiological effect of noribogaine. Specifically, the linkinggroup should be sufficiently stable in the circulatory system, but iscleaved to release the noribogaine upon entry into the brain. In oneembodiment, the linking group is at least 2 time and preferably at least10 times more reactive in the brain than in the circulatory system (i.e.in the blood or serum).

Suitable biocompatible, cleavable linking groups comprise a covalentbond and a linking group having from 1 to 20 atoms selected from carbon,nitrogen, oxygen, sulfur, and phosphorus, and are, in general,susceptible to cleavage conditions or agents in the brain (i.e. pH,redox potential or the presence of degradative molecules such asenzymes, e.g., proteases, lipases, etc.). Generally, the cleavageconditions or agents should be more prevalent or found at higher levelsor activities in the brain than in serum or blood. Examples ofdegradative agents include: redox agents which are selected forparticular substrates or which have no substrate specificity, including,e.g., oxidative or reductive enzymes or reductive agents such asesterases; enzymes that can hydrolyze or degrade an acid cleavablelinking group by acting as a general acid, peptidases (which can besubstrate specific), and phosphatases.

Biocompatible, cleavable ester-based linking groups are cleaved byenzymes such as esterases and amidases in the brain. Ester-basedcleavable linking groups comprise a cleavable ester group of the generalFormula —C(O)O— or —OC(O)—. Such ester-based groups can be cleaved byesterases, for example. Biocompatible, cleavable amide-based cleavablelinking groups comprise amide bonds formed between amino acids andincludes the amide group —C(O)NR— or —NRC(O)— where R can be hydrogen oralkyl. Amide-based cleavable linking groups can be cleaved by enzymessuch as peptidases and proteases. Biocompatible, cleavablephosphate-based cleavable linking groups are cleaved by agents thatdegrade or hydrolyze the phosphate group, such as phosphatases. Examplesof phosphate-based linking groups can include —P(O)(OR)—O—,—O—P(S)(OR)—O—, —O—P(S)(SR)—O—, —S—P(O)(OR)—O—, —O—P(O)(OR)—S—,—S—P(O)(OR)—S—, —O—P(S)(OR)—S—, —S—P(S)(OR)—O—, —O—P(O)(R)—O—,—O—P(S)(R)—O—, —S—P(O)(R)—O—, —S—P(S)(R)—O—, —S—P(O)(R)—S—,—O—P(S)(R)—S— where R can be hydrogen or alkyl. Exemplary linking groupsare shown in Scheme 2.

In general, the suitability of a candidate cleavable linking group canbe evaluated by testing the ability of a cleaving agent (or condition)to cleave the linking group. It will also be desirable to also test thelinking group for the ability to resist cleavage in the serum, blood orwhen in contact with other non-target tissue. Thus one can determine therelative susceptibility to cleavage between a first and a secondcondition, where the first is indicative of cleavage in the brain andthe second is indicative of cleavage in serum, blood or other non-targettissue. Such evaluations can be carried out in cell-free systems, incells, in cell culture, in organ or tissue culture, or in whole animals.In preferred embodiments, the cleavable linking group is cleaved atleast 2, 4, 10 or 100 times faster in the brain as compared to serum,blood or other non-target tissue.

Compounds of the Invention

In one embodiment of the present invention is provided a compound ofFormula I:

wherein

-   is a single or double bond;-   R is hydrogen, alkyl, —C(O)-alkyl, or the group -L-S where L is a    covalent bond or is a biocompatible, cleavable linking group and S    is a dehydrating saccharide or oligosaccharide;-   R¹ is hydrogen or the group -L-S where L is a covalent bond or is a    biocompatible, cleavable linking group and S is a dehydrating    saccharide or oligosaccharide; provided that at least one of R and    R¹ is -L-S;-   or a pharmaceutically acceptable salt thereof.

In a certain embodiment, R is hydrogen and R¹ is -L-S. In someembodiments, R is —C(O)-alkyl and R¹ is -L-S. In another embodiment, Ris -L-S and R¹ is hydrogen. In yet another embodiment, R and R¹ are-L-S.

In the present invention, S can be a saccharide or saccharide derivativesuch as an amino saccharide, provided that the sachharide is capable ofdisrupting or penetrating the BBB. For example, S can be a saccharide oramino saccharide from the group consisting of ethritol, zylitol,galactose, lactose, xylose, dulcitol, myo-insoitol, fructose, mannitol,sorbitol, glucose, arabinose, arabinose, celloboise, maltose, raffinose,rhamnose, melibiose, ribose, adonitol, arabitol, arabitol, fucose,lyxose, lyxose, lyxose, glucosamine, mannosamine, and galactosamine. Ina preferred embodiment, S is mannitol. In another preferred embodiment,S is glucose.

In one embodiment of the compounds of the present invention, R ishydrogen, mannopyranose, glucopyranose, glucopyranose-O—(CH₂)₉C(O)—,ribofuranose, ribopyranose or mannitol. In another embodiment, R¹ ishydrogen, glucopyranose-O—(CH₂)₈C(O)—, —C(O)O(CH₂CH₂O)₃CH₃, —CO₂CH₂CH₃or mannitol. In yet another embodiment, R is hydrogen, mannopyranose,glucopyranose, glucopyranose-O—(CH₂)₉C(O)—, ribofuranose, ribopyranoseor mannitol, and R¹ is hydrogen. In yet another embodiment, R ishydrogen and R¹ is hydrogen, glucopyranose-O—(CH₂)₈C(O)—,—C(O)O(CH₂CH₂O)₃CH₃ or —CO₂CH₂CH₃ or mannitol. In yet anotherembodiment, R and R¹ are mannitol.

In one embodiment of the compounds of the present invention,

is a single bond. In another embodiment,

is a double bond.

In one embodiment of the compounds of the present invention, L is asuitable biocompatible, cleavable linking group comprising from 1 to 20atoms selected from carbon, nitrogen, oxygen, sulfur, and phosphorus,and is, in general, susceptible to cleavage conditions or agents in thebrain. In one embodiment, the linking group is an ester-based linkinggroup. In another embodiment, the linking group is an amide-basedlinking group. In yet another embodiment, the linking group is aphosphate-based linking group. In another embodiment of the compounds ofthis invention, L is a covalent bond.

Also disclosed herein is a pharmaceutical composition comprising apharmaceutically acceptable excipient and a therapeutically acceptableof a compound of Formula I. In a certain embodiment, R is hydrogen andR¹ is -L-S. In some embodiments, R is —C(O)-alkyl and R¹ is -L-S. Inanother embodiment, R is -L-S and R¹ is hydrogen. In yet anotherembodiment, R and R¹ are -L-S. In a preferred embodiment, S is mannitol.In another preferred embodiment, S is mannose. In yet another preferredembodiment, S is glucose.

Specific compounds of Formula I which exemplify the present inventionare shown below in Table 1.

TABLE 1 No. Structure R R¹  1

Mannopyranose H  2

Glucopyranose H  3

Glucopyranose- O—(CH₂)₉C(O)— H  4

H Glucopyranose- O—(CH₂)₈C(O)—  5

Ribofuranose H  6

Glucopyranose —C(O)O— (CH₂CH₂O)₃— CH₃  7

ribopyranose H  8

Glucopyranose —CO₂CH₂CH₃  9

Mannitol H 10

Mannitol Mannitol

Compounds of the invention can be prepared from readily availablestarting materials using, for example, the following general methods andprocedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene, P. G. M. Wuts, Protective Groups in OrganicSynthesis, 4^(th) Edition, Wiley-Interscience, New York, 2006, andreferences cited therein. The starting materials for the followingreactions are generally known compounds or can be prepared by knownprocedures or obvious modifications thereof. For example, many of thestarting materials are available from commercial suppliers such asAldrich® Chemical Co. (Milwaukee, Wis., USA), Bachem (Torrance, Calif.,USA), Emka-Chemce or Sigma (St. Louis, Mo., USA). Others may be preparedby procedures, or obvious modifications thereof, described in standardreference texts such as Fieser and Fieser's Reagents for OrganicSynthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistryof Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier SciencePublishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, andSons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons,5th Edition, 2001), and Larock's Comprehensive Organic Transformations(VCH Publishers Inc., 1989).

Compounds of Formula I can be readily prepared from noribogaine bymethods known to one of skill in the art. Noribogaine can be synthesizedvia ibogaine O-demethylation. This may be accomplished, for example, byreacting ibogaine with boron tribromide/methylene chloride at roomtemperature and then purifying the product using known procedures. Inaddition, noribogaine may also be obtained from the National Instituteon Drug Abuse (Rockville, Md.). Ibogaine may be obtained from natural orcommercial sources, or can be synthesized by methods known in the art(see Huffman, et al., J. Org. Chem. 50:1460 (1985)).

For example, as shown in Scheme 1, noribogaine can be reacted with asaccharide-linking group conjugate (LG-L-S, where LG is a leaving groupsuch as alkoxy, halo, etc.) to form compounds of formula I. In certainembodiments (i.e. when R is H), the phenol is protected with a suitableprotecting group (PG-LG where LG is a leaving group such as alkoxy,halo, etc.) such that the indole nitrogen is derivatized with -L-S.Suitable protecting groups are well known in the art (see T. W. Greene,P. G. M. Wuts, Protective Groups in Organic Synthesis, 4^(th) Edition,Wiley-Interscience, New York, 2006). In an alternative embodiment (i.e.when R¹ is H), the indole nitrogen is protected with a suitableprotecting group (PG) (see Greene et al., supra) such phenol that isderivatized with -L-S. In another alternative embodiment, both theindole nitrogen and the phenol are both derivatized with -L-S groups.

Saccharide-linking group conjugates for use in the reactions depicted inScheme 1 (LG-L-S, where LG is a leaving group such as alkoxy, halo,etc.) can be synthesized using methods known in the art. The startingcompounds are commercially available from sources such as Aldrich®Chemical Company. For example, in one embodiment, the saccharide-linkinggroup conjugate for use in the reactions depicted in Scheme 1 is of theformula S—O—(CH₂)_(n)—CO—OCH₃ where S is the saccharide, n is an integerfrom 0 to 16 and —OCH₃ is the leaving group (LG) (Scheme 2, where R is Hor L-S) (see U.S. Pat. No. 5,877,187). In certain embodiments, n is aninteger from 5 to 10. The structures resulting from suchfunctionalization include the following (where for illustrative purposesonly α-D-mannopyranose is used as the saccharide):

Methods for preparing the compounds of Formula I wherein L is a covalentbond follow conventional saccharide chemistry. See, for example, U.S.Pat. No. 5,877,187 which is incorporated herein by reference in itsentirety. In one example, the anomeric carbon atom at the 1-position ofa saccharide is chemically modified by conventional techniques tointroduce a leaving group. Suitable leaving groups comprise halides,trichloroacetimidates, acetyl, thioglycosides, etc. The particularleaving group is selected relative to the functionality to which thesaccharide is to be attached. For example, in Scheme 1, attachment ofthe saccharide to the indole nitrogen of noribogaine can be accomplishedvia the hydroxyl protected compound leaving only the amino group tocouple with saccharide resulting in the formation of an N-linked sugar.Alternatively, coupling of the saccharide to the hydroxyl group wouldentail reacting the N-protected noribogaine with the appropriatefunctionalized sugar. Still further, using noribogaine and an excess offunctionalized saccharides would provide for both the O- andN-functionalized noribogaine. The structures resulting from suchfunctionalization include the following (where for illustrative purposesonly α-D-mannopyranose is used as the saccharide):

Exemplary compounds of this invention wherein L is a linking group canbe prepared by the synthetic protocols illustrated below in Scheme 3.

Noribogaine (3-1) can be modified with a saccharide-linking groupconjugate (3-2), or a protected derivative thereof (e.g., thepolyacetate or polybenzylate), to form a compound of formula I-1 underconventional amidation conditions well known in the art. Optionally, theindole nitrogen of 3-1 or the hydroxyl groups of 3-2 can be protectedusing suitable protecting groups prior to the reaction of 3-1 with 3-2and then subsequently deprotected using conditions known in the art.Compound 3-2 can be prepared from reacting at least a stoichiometricamount and preferably an excess of compound 3-4 with a suitablesaccharide (3-3). The reaction can be conducted under conventionalcoupling conditions well known in the art as the anomeric carbon atom ofthe saccharide will preferably react with the hydroxyl group of thelinker 3-2. In one embodiment, the reaction is conducted in a polarsolvent. Upon reaction completion, the compounds I-1 can be recovered byconventional techniques such as neutralization, extraction,precipitation, chromatography, filtration and the like; or,alternatively, used without purification and/or isolation.

Compounds 3-5 for use in the reactions depicted in Scheme 3, can beprepared by reacting compounds 3-6 (LG is preferably, but not limited toalkoxy or halo) with 3-1 under conventional esterification conditions.Optionally, the indole nitrogen of 3-1 can be protected using a suitableprotecting group prior to the reaction of 3-1 with 3-6 and thensubsequently deprotected using conditions known in the art. Compound 3-5can then be modified with 3-2 to form a compound of formula I-2 underconventional amidation conditions well known in the art. Upon reactioncompletion, I-2 can be recovered by conventional techniques such asneutralization, extraction, precipitation, chromatography, filtration,and the like; or, alternatively, used without purification and/orisolation.

Methods for preparing the compounds of Formula I-3 or I-4 wherein L is acovalent bond follow conventional saccharide chemistry. As Shown belowin Scheme 4, compounds of formula 4-1 can be prepared by the chemicalmodification of the anomeric carbon of 3-3 (e.g. mannose) byconventional techniques to introduce a leaving group LG (e.g. a halide,trichloroacetimidate, acetyl group, a thioglycoside, and the like). Theparticular leaving group is selected relative to the functionality towhich 4-1 is to be attached. The coupling of 4-1 to the indole nitrogenof 3-1 or 3-5 can be accomplished using typical coupling conditionsknown to one of skill in the art resulting in the formation of anN-linked sugar. Further, the hydroxyl groups of 3-3 or 4-1 can beprotected using a suitable protecting group and then subsequentlydeprotected using conditions known in the art. Upon reaction completion,I-3 or I-4 can be recovered by conventional techniques such asneutralization, extraction, precipitation, chromatography, filtration,and the like; or, alternatively, used without purification and/orisolation.

Alternatively, as shown in Scheme 5, coupling of the saccharide to thephenol moiety of 3-1 can proceed via reacting 3-1 with the appropriatelyfunctionalized 4-1. Although not shown, it is contemplated that 3-1 maycouple with the anomeric carbon atom of 3-3 under certain reactionconditions without the need for a leaving group. Optionally, the indolenitrogen of 3-1 or the hydroxyl groups of 4-1 or 3-3 can be protectedusing suitable protecting groups (e.g., the hydroxyl groups of 4-1 canbe protected as the polyacetate or polybenzylate), and then subsequentlydeprotected using conditions known in the art.

Chemical reactions as described above are known in the art and areexemplified in U.S. Pat. Nos. 5,877,157 and 6,174,867, which areincorporated herein by reference in their entirety.

Methods of the Invention

Noribogaine, a metabolite of ibogaine, has properties that are wellsuited to the treatment of pain and to the withdrawal symptomsassociated with drug dependency or abuse. In particular, it has beendiscovered that noribogaine binds to two classes of opioid receptorsthat have been associated with pain relief, the μ and κ receptors. Inthe case of the μ-type receptors, it appears that noribogaine acts as afull opiate agonist. In addition, noribogaine elevates brain serotoninlevels by blocking synaptic reuptake. It is believed that such levels(as well as ligand interactions at the μ and κ opiate receptors) play arole in the anxiety and drug cravings experienced by addicts duringwithdrawal.

Treatment of Pain

One aspect of the present invention is directed to a method for treatingpain in a patient. The pain can be any type of pain including, but notlimited to neuropathic or nociceptive pain, and various types thereofincluding somatic, visceral and phantom pain. Accordingly, in oneembodiment, the method comprises administering to said patient apharmaceutical composition comprising a therapeutically effective amountof noribogaine, or a derivative or pharmaceutically acceptable saltthereof, and an effective amount of a pharmaceutically acceptableexcipient to enhance the blood brain barrier penetration of noribogaine.

In another embodiment, the present invention is directed to a method fortreating pain in a patient which method comprises administering to saidpatient a therapeutically effective amount of a compound of Formula I ora pharmaceutical composition comprising a therapeutically effectiveamount of a compound of Formula I and a pharmaceutically acceptableexcipient.

Treatment of Addiction

Noribogaine has been known to be used to treat patients for alleviatingthe symptoms associated with withdrawal from drug dependency.Accordingly, the present invention is also directed to a method fortreating addiction in a patient which method comprises administering tosaid patient a pharmaceutical composition comprising a therapeuticallyeffective amount of noribogaine, or a derivative or pharmaceuticallyacceptable salt thereof, and an effective amount of a pharmaceuticallyacceptable excipient to enhance the blood brain barrier penetration ofnoribogaine. In another embodiment, the invention is directed to amethod for treating addiction in a patient which method comprisesadministering to said patient a therapeutically effective amount of acompound of Formula I or a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula I and apharmaceutically acceptable excipient.

In certain embodiments, the treatment of addiction in a patientcomprises alleviating the symptoms associated with withdrawal from drugdependency. Such symptoms include nausea, vomiting, anxiety, abdominalcramps, muscle pain, chills and headache. In addition, noribogainetreatment decreases the drug cravings normally experienced by addictsafter cessation of the self administration of the abused substance. Itis contemplated that the compositions disclosed herein are especiallyuseful in the treatment of addiction to narcotics such as heroin andmethadone. However, it is also useful in treating patients addicted tococaine, alcohol, amphetamines and combinations of these drugs.

Dosage and Routes of Administration

It is contemplated that any route of administration and dosage form maybe compatible with the pharmaceutical compositions and methods discussedabove. As the compositions disclosed herein are designed to target thebrain and penetrate the blood brain barrier, it is contemplated that thedosage of noribogaine administered to the patent can be decreased incomparison to the dose administered to a patient when using noribogainealone. That said, the appropriate dosing regimen and route ofadministration can be readily determined by the attending clinician.

Although compositions suitable for oral, intravenous or intraarterialdelivery will probably be used most frequently, other routes that may beused include peroral, pulmonary, rectal, nasal, vaginal, lingual,intramuscular, intraperitoneal, intracutaneous and subcutaneous routes.In addition, it is contemplated that the composition can be administeredtransdermally in which drug is applied as part of a cream, gel, or patch(for examples of transdermal Formulations, see U.S. Pat. Nos. 4,806,341;5,149,538; and 4,626,539). Other dosage forms include tablets, capsules,pills, powders, aerosols, suppositories, parenterals, and oral liquids,including suspensions, solutions and emulsions. Sustained release dosageforms may also be used. All dosage forms may be prepared using methodsthat are standard in the art (see e.g., Remington's PharmaceuticalSciences, 16th ed., A. Oslo editor, Easton Pa. 1980).

The compositions disclosed herein may be used in conjunction with any ofthe vehicles and excipients commonly employed in pharmaceuticalpreparations, e.g., talc, gum arabic, lactose, starch, magnesiumstearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffinderivatives, glycols, etc. Coloring and flavoring agents may also beadded to preparations, particularly to those for oral administration.Solutions can be prepared using water or physiologically compatibleorganic solvents such as ethanol, 1,2-propylene glycol, polyglycols,dimethylsulfoxide, fatty alcohols, triglycerides, partial esters ofglycerine and the like. Parenteral compositions containing noribogainemay be prepared using conventional techniques that may include sterileisotonic saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol,polyglycols mixed with water, Ringer's solution, etc.

It is contemplated that the dosage required for treating pain may differfrom the dosage required for treating addiction, however, the dosingregimen can be readily determined by the attending clinician based onthe desired treatment. It is contemplated that for the treatment ofpain, the dosage of noribogaine administered to a patient may be fromabout 0.1 to about 100 mg per kg of body weight and, preferably, fromabout 0.1 to about 30 mg per kg of body weight. For the treatment ofaddiction, the dosage of noribogaine administered to a patient may befrom about 0.1 to about 20 mg/ml.

Kit of Parts

One aspect of the present invention is directed to a kit of partscomprising a composition as disclosed herein and a means foradministering the composition to a patient in need thereof. The meansfor administration to a patient can include, for example, any one orcombination of a syringe, a needle, an IV bag comprising thecomposition, a vial comprising the composition, etc. In one embodiment,the kit comprises a first and a second vial, wherein the first vialcomprises the pharmaceutically acceptable excipient to enhance the bloodbrain barrier penetration of noribogaine and the second compositioncomprises a therapeutically effective amount of noribogaine, or aderivative or pharmaceutically acceptable salt thereof. In such anembodiment, the pharmaceutically acceptable excipient may beadministered to the patient just prior to the noribogaine composition.In one embodiment, the pharmaceutically acceptable excipient isadministered to the patient about 5 to 10 minutes prior to thenoribogaine composition.

EXAMPLES

The present invention is further defined by reference to the followingexamples. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced withoutdeparting from the scope of the current invention.

TABLE 2 List of abbreviations and acronyms. Abbreviation Meaning ° C.Degree Celsius {acute over (Å)} Angstrom Ac Acetyl aq. Aqueous atmAtmosphere Bn Benzyl bs Broad singlet Bu Butyl d Doublet DCMdichloromethane dd Doublet of doublets DMAP 4-Dimethylaminopyridine DMFDimethylformamide Et Ethyl g Gram h Hour HPLC High-performance liquidchromatography Hz Hertz i-Pr Isopropyl IV Intravenous Kg Kilogram MMolar m Multiplet M+ Mass peak Me Methyl mg Milligram min Minute mLMilliliter mM Millimolar mmol Millimole MS Mass spectrometry N NormalNaHDMS Sodium hexamethyldisilazane NMR Nuclear magnetic resonance PEGPolyethylene glycol prep Preparative r.t./rt Room temperature s Singlett Triplet TBS tert-Butyldimethylsilyl TBSCl tert-Butyldimethylsilylchloride t-Bu tert-Butyl THF Tetrahydrofuran TLC Thin layerchromatography Ts p-Toluenesulfonyl v/v Volume/volume δ Chemical shiftμL Microliter

Example 1 Preparation of Compound 1

Preparation of bromide 1-A

To a solution of 1,2,3,4,6-penta-O-acetyl-D-mannopyranose (1 g, 2.56mmol) in DCM (2 mL) was added HBr (33% in AcOH, 2.5 mL) dropwise at roomtemperature. The reaction mixture was stirred at room temperature for 2h. The mixture was diluted with DCM, and washed with H₂O and NaHCO₃(3×). The organic layer was dried and concentrated. The crude 1-A (1.06g, 100%) was pure enough to be used directly in the next step withoutfurther purification.

Preparation of 1

To a solution of noribogaine HCl salt (30 mg, 0.09 mmol) and bromide 1-A(74 mg, 0.18 mmol) in MeOH (2 mL) was added portionwise LiOH.H₂O (15 mg,0.36 mmol). The reaction mixture was stirred at room temperature for 2h. The solution was acidified to neutral with aq. HCl (0.5 N). Themixture was purified by prep-HPLC to give compound 1 (10 mg) as a whitesolid.

MS calculated for (C₂₅H₃₄N₂O₆): 458.2; MS found (M+1): 459.3. ¹H NMR(CD₃OD) δ 8.52 (bs, 1H), 7.25 (d, 1H), 7.17 (d, 1H), 6.88 (dd, 1H), 5.38(d, 1H), 4.02 (d, 1H), 3.93 (dd, 1H), 3.80-3.62 (m, 5H), 3.60 (m, 3H),3.41 (m, 3H), 3.22 (m, 1H), 2.36 (t, 1H), 2.19 (m, 2H), 2.00 (m, 1H),1.76 (dd, 1H), 1.62 (m, 2H), 1.40 (m, 1H), 1.02 (t, 3H).

Example 2 Preparation of Compound 2

Preparation of 2-A

To a solution of penta-acetyl-alpha-D-glucose (3.9 g, 10 mmol) and1,9-nonanediol (2.4 g, 15 mmol) in DCM (35 mL) was added dropwise SnCl₄(15 mmol, 1M in DCM, 15 mL). The resulting mixture was stirred at 50° C.for 4 h. The reaction mixture was diluted with DCM and H₂O. The organiclayer was separated, washed with NaHCO₃, and dried and concentrated. Thecrude product mixture was purified by flash column chromatography(EtOAc:Hexanes/1:1) to afford compound 2-A (1.6 g, 33%).

MS calculated for (C₂₃H₃₈O₁₁): 490; MS found (M+1): 491

Preparation of 2-B

To a solution of 2-A (200 mg, 0.40 mmol) and N,N′-disuccinimidylcarbonate (122 mg, 0.48 mmol) in chloroform (2 mL) was added pyridine(0.042 mL, 0.52 mmol) in one portion. The mixture was stirred at rt for3 h. Aqueous HCl (0.5 N) was used to quench the reaction. The reactionwas diluted with DCM and H₂O. The organic layer was extracted, dried andconcentrated to give crude compound 2-B in quantitative yield, whichused in the next step without purification.

MS calculated for (C₂₈H₄₁NO₁₅): 631; MS found (M+1): 632

Preparation of 2-C

To a solution of 2-B (crude, 0.4 mmol) and noribogaine HCl salt (35 mg,0.08 mmol) in DCM (2 mL) was added DMAP (112 mg, 0.92 mmol) and DIPEA(60 μL, 0.36 mmol). The reaction mixture was stirred at 40° C. for 1 h.The reaction solution was diluted with DCM and H₂O. The organic layerwas separated, dried and concentrated, and the crude product purified byprep-TLC (DCM:MeOH, 8:1) to give product 2-C (60 mg, 92%).

MS calculated for (C₄₃H₆₀N₂O₁₃): 812; MS found (M+1): 813

Preparation of 2

To a solution of compound 2-C (20 mg, 0.024 mmol) in THF/H₂O (2 mL:1 mL)was added LiOH (6 mg, 0.143 mmol). The reaction mixture was stirred atrt for 2 h. The reaction mixture was then acidified to neutral with 1 Naq. HCl. The crude mixture was purified by HPLC to give compound 2 (9mg).

MS calculated for (C₃₅H₅₂N₂O₉): 644.4; MS found (M+1): 645.6. ¹H NMR(CD₃OD) δ 8.52 (bs, 1H), 7.25 (m, 2H), 6.87 (dd, 1H), 4.76 (d, 1H), 4.22(t, 2H), 3.80-3.50 (m, 8H), 3.42-3.35 (m, 5H), 3.25-3.08 (m, 2H), 2.32(t, 1H), 2.14 (m, 2H), 2.03 (m, 1H), 1.77-1.58 (m, 7H), 1.48-1.32 (m,11H), 1.02 (t, 3H).

Example 3 Preparation of Compound 3

Preparation of 3-A

To a solution of penta-acetyl-alpha-D-glucose (1.0 g, 2.56 mmol) in DCM(2 mL) was added HBr (33% in AcOH, 2.5 mL) dropwise at room temperature.The reaction mixture was stirred at room temperature for 2 h. Themixture was then diluted with DCM, and washed with H₂O and NaHCO₃ (3×).The organic layer was dried and concentrated to giver crude bromide 3-A(1.06 g, 100%), which was used directly in the next step withoutpurification.

Preparation of 3

To a solution of noribogaine HCl salt (30 mg, 0.09 mmol) and bromide 3-A(74 mg, 0.18 mmol) in MeOH (2 mL) was added portionwise LiOH.H₂O (15 mg,0.36 mmol). The reaction mixture was stirred at room temperature for 2h, then the solution was acidified to neutral with 0.5 N aq. HCl. Themixture was purified by prep HPLC to give compound 3 (11 mg) as a whitesolid.

MS calculated for (C₂₅H₃₄N₂O₆): 458.2; MS found (M+1): 459.3. ¹H NMR(CD₃OD) δ 8.47 (bs, 1H), 7.24 (d, 1H), 7.17 (d, 1H), 6.94 (dd, 1H), 4.84(d, 1H), 3.94 (d, 1H), 3.70 (dd, 1H), 3.62-3.54 (m, 3H), 3.42-3.38 (m,4H), 3.36 (m, 3H), 3.20 (m, 2H), 2.30 (t, 1H), 2.13 (m, 2H), 1.99 (m,1H), 1.77-1.58 (m, 3H), 1.39 (m, 1H), 1.03 (t, 3H).

Example 4 Preparation of Compound 4

Preparation of TBS-Noribogaine 4-A

A suspension of noribogaine HCl (852 mg, 2.56 mmol), TBSCl (444 mg, 2.94mmol) and imidazole (227 mg, 3.33 mmol) in DMF (6 mL) was stirred atroom temperature for 20 h. The resulting clear solution was diluted with10% 2-propanol/dichloromethane and washed with water (3×) and brine. Theaqueous phase was extracted with EtOAc. The combined organic layers wereconcentrated and purified by column chromatography (EtOAc/Hexanes, v/v,2/1). Pure 4-A (911 mg, 87%) was obtained as a white solid.

MS calculated for (C₂₅H₃₈N₂OSi): 410, MS found (M+1): 411.

Preparation of 9-Hydroxy-Nonanoic Acid Methyl Ester 4-B

To a solution of nonanedioic acid monomethyl ester (4.80 g, 20 mmol) inTHF (20 mL) at −20° C. was added a solution of borane-dimethylsulfide inTHF (2.0 M, 10 mL) over 10 min. The resulting mixture was stirred for anadditional 10 min, and then allowed to stir at room temperatureovernight. Aqueous K₂CO₃ solution was added, and the product wasextracted with ethyl ether (3×). The crude product was purified by flashcolumn chromatography (hexane/EtOAc:2/1) to yield 9-hydroxy-nonanoicacid methyl ester 4-B (2.0 g, 55%).

¹H NMR (CDCl₃) δ 4.86 (bs, 1H, OH), 3.67 (s, 3H), 3.63 (t, J=7.4 Hz,2H), 2.29 (t, J=7.4 Hz, 2H), 1.68-1.48 (m, 4H), 1.40-1.24 (m, 8H).

Preparation of 4-C

A mixture of 2,3,4,6-tetra-O-benzyl-D-glucopyranose (2.0 g, 3.7 mmol),trichloroacetonitrile (2.13 g, 14.8 mmol) and K₂CO₃ (0.66 g, 4.8 mmol)in DCM (13 mL) was stirred at room temperature for 3 days. The solid wasremoved by filtration and the filtrate was concentrated to provide acrude product 4-C (3.0 g, >100%) which was used without purification.

MS calculated for (C₃₆H₃₆Cl₃NO₆): 683.2; MS found (M+Na): 708

Preparation of 4-D

A solution of SnCl₄ in DCM (1.0 M, 1.2 mL) was slowly added into asolution of 4-B (230 mg, 1.22 mmol) and 4-C (1.25 g, 1.83 mmol) in DCM(3.5 mL) at 0° C. The resulting mixture was stirred at the temperaturefor 20 min, and then water was added to quench the reaction. The productwas extracted with DCM, and the crude product was purified by flashcolumn chromatography (EtOAc/hexane:1/4) to afford 4-D (400 mg, 46%).

MS calculated for (C₄₄H₅₄O₈): 710; MS found (M+Na): 733

Preparation of 4-E

A mixture of 4-D (400 mg, 0.56 mmol), LiOH (118 mg, 2.81 mmol) inMeOH/water/THF (2 mL/2 mL/4 mL) was stirred at room temperature for 16h. The solution was acidified with 1 N aq. HCl to pH˜3.0. The productwas extracted with ethyl acetate, and the combined organic layers weredried over MgSO₄. After filtration and concentration, the crude product4-E (0.39 g, quantitative) was used for next reaction withoutpurification.

¹H NMR (CDCl₃) δ 7.40-7.12 (m, 17H), 7.08-7.05 (m, 3H), 5.02-4.38 (m,8H), 4.00-3.92 (m, 1H), 3.78-3.38 (m, 8H), 2.34 (t, J=7.4 Hz, 2H),1.68-1.55 (m, 4H), 1.40-1.24 (m, 8H).

Preparation of 4-F

Oxalyl chloride (59 μL, 0.68 mmol) was slowly added into a solution ofacid 4-E (0.39 g, 0.57 mmol) in DCM (5 mL) at room temperature, followedby adding DMF (7 μL). The resulting mixture was stirred at thetemperature for 3 h, and then concentrated. The crude product 4-F wasfurther dried under high vacuum and used in next reaction withoutpurification.

Preparation of 4-G

A solution of acyl chloride 4-F (104 mg, 0.25 mmol) in THF (2 mL) wascooled at −78° C., and then 0.38 mL of 1 N NaHMDS in THF was added.After 15 min a solution of 4-A (274 mg, 0.38 mmol) in THF (3 mL) wasadded. The reaction mixture was stirred at −78° C. for 20 min, and thenallowed to slowly warmed up to room temperature. The reaction wasquenched with saturated NH₄Cl solution after 2 h. The product wasextracted with DCM. After combination and concentration of the extracts,the crude product was purified by prep-TLC to afford 4-G (110 mg).

MS calculated for (C₆₈H₈₈N₂O₈Si): 1089; MS found (M+H): 1090

Preparation of 4-H

Hydrogenation of 4-G (110 mg, 0.10 mmol) was carried in EtOAc/MeOH (2mL/3 mL) with 10% Pd/C (80 mg) as catalyst under 1 atm of hydrogen,using HCl (4 N in dioxane, 100 μL) to acidify the solution. After 48 hthe mixture was filtered through a pad of Celite, and the organic layerconcentrated. The crude product was purified by prep-TLC to give 4-H (17mg, 27%).

MS calculated for (C₄₀H₆₄N₂O₈Si): 728; MS found (M+H): 729

Preparation of 4

TBS-protected 4-H (17 mg, 0.023 mmol) was further de-protected withBu₄NF (40 mg, 1.08 mmol) in MeOH (3 mL) at 50° C. The reaction wascomplete after 3 h. The crude product was purified by prep-TLC to affordthe pure compound 4 (12 mg).

MS calculated for (C₃₄H₅₀N₂O₈): 614; MS found (M+H): 615. ¹H NMR (CD₃OD)δ 7.56 (d, J=8.7 Hz, 1H), 6.88 (d, J=2.4 Hz, 1H), 6.79 (dd, J=8.7 Hz,and 2.4 Hz, 1H), 4.78 (d, J=2.1 Hz, 0.5; H), 4.26 (d, J=7.8 Hz, 0.5H),3.94-3.12 (m, 14H), 3.10-2.96 (m, 2H), 2.26-2.10 (m, 2H), 2.08-1.72 (m,4H), 1.70-1.54 (m, 5H), 1.50-1.34 (m, 11H), 1.00 (t, J=7.2 Hz, 3H).

Example 5 Preparation of Compound 5

Preparation of 5-A

A mixture of noribogaine (17 mg, 0.06 mol),tetra-O-acetyl-β-D-ribofuranose (38 mg, 0.12 mmol) and 4 Å molecularsieves (1 g) in DCM (2 mL) was stirred at room temperature for 10 min.Boron trifluoride etherate complex (200 μL, 1.6 mmol) was added, andresulting mixture was stirred at the temperature for 2 h. The reactionmixture was diluted with DCM and then filtered to remove the solid. Thefiltrate was concentrated and further dried in high vacuum. The crudeproduct was purified by flash column chromatography(Et₃N/i-PrOH/DCM:1/10/200) to yield 7 mg of 5-A.

MS calculated for (C₃₀H₃₈N₂O₈): 554; MS found (M+H): 555

Preparation of 5

Esterase (from porcine liver) suspension (1 drop) was added into asolution of the triacetate 5-A (7 mg, 0.013 mmol) in 10 mL of phosphatebuffer (10 mM, pH 8.0). The reaction mixture was stirred at 25° C. for 7h, and then treated with 10 mL of MeOH. The resulting solution wasconcentrated to 3 mL and purified by prep-HPLC to yield 2.5 mg of thepure compound 5.

MS calculated for (C₂₄H₃₂N₂O₅): 428; MS found (M+H): 429. ¹H NMR (CD₃OD)δ 7.16 (d, J=8.7 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 6.81 (dd, J=8.7 and2.4 Hz, 1H), 5.49 (d, J=1.2 Hz, 1H), 4.25-4.17 (m, 2H), 4.12-4.04 (m,1H), 3.82-3.76 (m, 1H), 3.70-3.48 (m, 4H), 3.40-3.08 (m, 3H), 2.38-2.24(m, 1H), 2.18-1.92 (m, 4H), 1.78-1.58 (m, 3H), 1.40-1.26 (m, 3H), 1.03(t, J=7.2 Hz, 3H).

Example 6 Preparation of Compound 6

Preparation of 6-A

A mixture of noribogaine (42 mg, 0.15 mol), 1,2,3,4-tetraacetateβ-D-ribopyranose (95 mg, 0.30 mmol) and 4 Å molecular sieves (2 g) inDCM (5 mL) was stirred at room temperature for 10 min. Boron trifluorideetherate complex (500 μL, 4.0 mmol) was added, and resulting mixture wasstirred at the temperature for 2 h. The reaction mixture was dilutedwith DCM and then filtered. The filtrate was concentrated and furtherdried under high vacuum. The crude product was purified by flash columnchromatography (Et₃N/i-PrOH/DCM:1/10/200) to yield 6-A (30 mg).

MS calculated for (C₃₀H₃₈N₂O₈): 554; MS found (M+H): 555

Preparation of 6

Esterase (from porcine liver) suspension (1 drop) was added into asolution of the triacetate 6-A (30 mg, 0.054 mmol) in 20 mL of phosphatebuffer (10 mM, pH 8.0). The reaction mixture was stirred at 25° C. for96 h, and then treated with 20 mL of MeOH. The resulting solution wasconcentrated to 3 mL purified by on prep HPLC to yield 7.0 mg of thepure compound 6.

MS calculated for (C₂₄H₃₂N₂O₅): 428; MS found (M+H): 429. ¹H NMR (CD₃OD)δ 7.18 (d, J=8.7 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.87 (dd, J=8.7 and2.1 Hz, 1H), 5.37 (d, J=3.9 Hz, 1H), 4.03 (m, 1H), 3.96-3.50 (m, 8H),3.43-3.08 (m, 3H), 2.38-2.24 (m, 1H), 2.18-1.96 (m, 6H), 1.80-1.58 (m,3H), 1.46-1.26 (m, 2H), 1.05 (t, J=7.5 Hz, 3H).

Example 7 Preparation of Compound 7

Preparation of TBS-noribogaine-PEG 7-A

NaHMDS (0.6 mL, 1.0 M solution in THF) was added into a solution ofTBS-noribogaine 4-A (164 mg, 0.4 mmol) in THF (8 mL) at −78° C. Theresulting solution was stirred for 10 min at −78° C. before a solutionof 4-nitrophenyl chloroformate (126 mg, 0.6 mmol) in THF (6 mL,pre-cooled to −78° C.) was added quickly. The reaction mixture waswarmed up to room temperature and stirred for 30 min before it was againcooled back to −78° C. NaHMDS (0.8 mL, 1.0 M solution in THF) was addedto a solution of triethyleneglycol methyl ether (0.125 mL, 0.8 mmol) inTHF (6 mL) at −78° C. The resulting solution was warmed up to roomtemperature and stirred for 10 min. This solution of deprotonated PEGalcohol was then added into the above reaction mixture at −78° C. viasyringe. After stirring at room temperature for one hour, the reactionmixture was partitioned between dichloromethane and water. The layerswere separated, and the aqueous phase was extracted with EtOAc. Thecombined organic layers were washed with brine and dried over Na₂SO₄.After concentration the crude product was purified by columnchromatography (EtOAc/hexanes, v/v, 1/1 to pure EtOAc). The desiredproduct 7-A (114 mg) was obtained as a yellow oil.

MS calculated for (C₃₃H₅₂N₂O₆Si): 600, MS found (M+1): 601.

Preparation of 7-B

TBAF (0.48 mL, 1.0 M solution in THF) was added to a solution of 7-A(114 mg, 0.19 mmol) in THF (5 mL) at −78° C. The resulting solution wasstirred for 15 min at −78° C. and 40 min at room temperature before itwas concentrated and purified by column chromatography(dichloromethane/2-propanol/triethylamine, v/v, 10/1/0 to 100/20/1). Theresulting product was further purified by prep-HPLC to give pure 7-B (68mg) as a slightly yellow solid.

MS calculated for (C₂₇H₃₈N₂O₆): 486, MS found (M+1): 487. ¹H NMR (CD₃CN)δ 10.75 (bs, 1H), 8.05 (d, 1H), 7.62 (bs, 1H), 7.03 (s, 1H), 6.95 (d,1H), 4.55-4.73 (m, 2H), 4.12 (dd, 1H), 3.86-4.06 (m, 3H), 3.48-3.85 (m,11H), 3.36 (s, 3H), 3.05-3.25 (m, 3H), 2.63 (t, 1H), 2.20-2.45 (m, 4H),1.90-2.20 (m, 1H), 1.76-1.95 (m, 2H), 1.54 (d, 1H), 1.02-1.18 (m, 3H).

Preparation of 7

Phenol 7-B (65 mg, 0.134 mmol), tetra-acetyl glucose bromide 3-A (110mg, 0.267 mmol) and LiOH monohydrate (23 mg, 0.53 mmol) were dissolvedin MeOH (3 mL). The solution was stirred at room temperature for onehour before more 3-A (60 mg) and LiOH monohydrate (11 mg) were added.After stirring one additional hour, the reaction was quenched by adding1N aq. HCl (0.9 mL). Prep-HPLC purification afforded compound 7 (12.9mg) as a white solid.

MS calculated for (C₃₃H₄₈N₂O₁₁): 648, MS found (M+1): 649. ¹H NMR(CD₃CN) δ 8.00 (d, 0.5; H), 7.92 (d, 0.5; H), 7.16-7.23 (m, 1H),7.00-7.08 (m, 1H), 4.94 (d, 1H), 4.45-4.62 (m, 1H), 3.90-4.05 (m, 2H),3.70-3.90 (m, 3H), 3.25-3.70 (m, 22H), 3.26 (s, 3H), 3.05-3.22 (m, 3H),2.40-2.58 (m, 1H), 2.18 (bs, 1H), 1.85-2.05 (m, 1H), 1.30-1.76 (m, 4H),0.96 (t, 3H).

Example 8 Preparation of Compound 8

Preparation of 8-A

A solution of compound 4-A (102 mg, 0.25 mmol) in THF (3 mL) was cooledat −78° C., and then 0.38 mL of 1 N NaHMDS in THF was added. After 15min, a solution of ethyl chloroformate (48 μL, 0.50 mmol) was added. Thereaction mixture was stirred at −78° C. for 20 min, and then slowlywarmed up to room temperature. The reaction was quenched with waterafter 2 h. The product was extracted with DCM, and the combined organicextracts were dried over MgSO₄. Concentration of the filtrate, finallyunder high vacuum afforded pure compound 8-A (120 mg).

MS calculated for (C₂₈H₄₂N₂O₃Si): 482, MS found (M+1): 483.

Preparation of 8-B

A solution of Bu₄NF in THF (1.0 M, 0.50 mL) was added into a solution ofcompound 8-A (0.12 mg, 0.25 mmol) in THF (5 mL) at −78° C. The resultingmixture was stirred at −78° C. for 30 min and then at room temperaturefor 1 h. A few drops of 1 N aq. HCl were added to quench the reaction.The reaction mixture was concentrated, and the residue was purified bychromatography on silica gel using NEt₃/iPrOH/DCM (2/10/200) as eluentto give compound 8-B (69 mg, 75%).

MS calculated for (C₂₂H₂₈N₂O₃): 368, MS found (M+1): 369.

Preparation of 8

LiOH (32 mg, 0.75 mmol) was added into a solution of 8-B (69 mg, 0.19mmol) and 1-bromo-2,3,4,6-tetra-O-acetyl-glucopyranose (156 mg, 0.38mmol) in MeOH (4 mL). The resulting mixture was stirred at roomtemperature for 1 h. The reaction was quenched by adding a few drops of1 N aq, HCl. The crude product was purified by prep-HPLC to givecompound 8 (20 mg, 20%).

MS calculated for (C₂₈H₃₈N₂O₈): 530, MS found (M+1): 531. ¹H NMR (CD₃OD)δ 7.95 (d, J=9.0 Hz, 1H), 7.25 (d, J=2.1 Hz, 1H), 7.09 (dd, J=2.1 and9.0 Hz, 1H), 4.49 (t, J=7.2 Hz, 2H), 4.18-4.08 (m, 1H), 3.96-3.82 (m,3H), 3.74-3.64 (m, 1H), 3.60-3.40 (m, 5H), 3.38-3.28 (m, 3H), 3.26-3.12(m, 3H), 2.68-2.54 (m, 1H), 2.21 (bs, 1H), 2.14-1.96 (m, 2H), 1.72-1.42(m, 6H), 1.05 (t, J=7.2 Hz, 3H).

Example 9 Preparation of Compounds 9 and 10

Preparation of 9-C

A solution of 3,4-O-isopropylidene-D-mannidol 9-A (5.0 g, 22.5 mmol),2-methoxypropene 9-B (1.62 g, 22.5 mmol) and TsOH (192 mg, 1.1 mmol) inDMF (20 mL) was stirred at room temperature for 18 hours. The reactionmixture was concentrated and purified by flash column chromatography(DCM/EtOAc, v/v, 1/1 to 1/3) to afford 9-C as a crystalline solid (3.99g).

MS calcd for (C₁₂H₂₂O₆): 262; MS found (M+Na): 285.

Preparation of 9-D

Benzoyl chloride (1.76 mL, 15.2 mmol) was added dropwise to a solutionof 1,2,3,4-O-diisopropylidene-D-mannidol 9-C (3.99 g, 15.2 mmol) inpyridine (20 mL) and DCM (50 mL) at −78° C. The reaction mixture wasstirred for one hour and then allowed to warm up to 0° C. After 1.5hours, the resulting mixture was poured into 150 mL of ice-cooled aq. 5NHCl, and extracted with DCM. The organic extract was washed with water,saturated NaHCO₃, and brine. After drying over Na₂SO₄ and concentration,5.3 g of a colorless oil was obtained.

The crude oil, DMAP (186 mg, 1.52 mmol) and Et₃N (2.55 mL, 18.3 mmol)were dissolved in 30 mL DCM and cooled to 0° C. TsCl (3.19 g, 16.7 mmol)was added, and the resulting solution was stirred for one hour at 0° C.and 18 hours at room temperature. The solution was then cooled to 0° C.,and ice-cold aq. 3N HCl (20 mL) was added. The layers were separated,and the organic extract was washed with brine and dried over Na₂SO₄.Concentration afforded 8.3 g of a brown oil.

The crude oil was treated with K₂CO₃ (5.2 g) in DCM (40 mL) and MeOH (45mL) at room temperature for 3 hours. Water (20 mL) was added into thesolution. The organic layer was separated and washed with sat. NH₄Cl.After drying over Na₂SO₄ and concentration, the residue was purified byflash column chromatography (EtOAc/toluene, v/v, 1/4) to afford 9-D as awhite crystalline solid (1.6 g).

¹H NMR (300 MHz, CDCl₃) δ 3.80-4.24 (m, 5H), 3.10 (q, 1H), 2.80 (d, 2H),1.41 (s, 3H), 1.39 (s, 3H), 1.38 (s, 3H), 1.34 (s, 3H).

Preparation of 9-E and 9-F

Epoxide 9-D (91 mg, 0.36 mmol) was added into a solution of noribogaine(90 mg, 0.3 mmol, free base) and t-BuOK (34 mg, 0.3 mmol) in 6 mL of DMFat room temperature. The reaction mixture was heated at 150° C. for 30min in a microwave reactor. The resulting dark solution was diluted withDCM and washed with water (2×) and dried over Na₂SO₄. The mixture waspurified by preparative TLC (2-propanol/DCM, v/v, 1/10) to afford 9-E(25 mg) and 9-F (35 mg), both as pale white solids.

MS calcd for 9-E (C₃₁H₄₄N₂O₆): 540; MS found (M+1): 541.

MS calcd for 9-F (C₄₃H₆₄N₂O₁₁): 784; MS found (M+1): 785.

Preparation of 9

Compound 9-E (21 mg) was treated with aq. 3N HCl (1 mL) in MeOH (3 mL)at room temperature for 20 hours. The resulting solution was directlypurified by reverse-phase preparative HPLC to afford 9 (11.3 mg) as awhite solid.

MS calcd for (C₂₅H₃₆N₂O₆): 460; MS found (M+1): 461. ¹H NMR (300 MHz,CD₃OD) δ 7.17 (d, 1H), 7.00 (d, 1H), 6.80 (dd, 1H), 4.00-4.20 (m, 4H),3.50-3.82 (m, 7H), 3.10-3.45 (m, 5H), 2.30 (t, 1H), 1.90-2.20 (m, 3H),1.55-1.76 (m, 3H), 1.30-1.42 (m, 1H), 1.04 (t, 3H).

Preparation of 10

Compound 9-F (26 mg) was treated with aq. 3N HCl (1 mL) in MeOH (3 mL)at room temperature for 20 hours. The resulting solution was directlypurified by reverse-phase preparative HPLC to afford 10 (12 mg) as awhite solid.

MS calcd for (C₃₁H₄₈N₂O₁₁): 624; MS found (M+1): 625. ¹H NMR (300 MHz,CD₃OD) δ 7.24 (d, 1H), 6.93 (d, 1H), 6.78 (dd, 1H), 4.40-4.58 (m, 1H),4.20-4.30 (m, 1H), 3.90-4.10 (m, 6H), 3.28-3.75 (m, 14H), 2.92-3.25 (m,2H), 2.34 (t, 1H), 1.95-2.12 (m, 3H), 1.40-1.70 (m, 3H), 1.25-1.40 (m,1H), 0.97 (t, 3H).

What is claimed is:
 1. A compound of Formula I:

wherein R is hydrogen, alkyl, —C(O)-alkyl, or the group -L-S where L isa covalent bond or is a biocompatible, cleavable linking group and S isa dehydrating saccharide or oligosaccharide; R¹ is hydrogen or the group-L-S where L is a covalent bond or is a biocompatible, cleavable linkinggroup and S is a dehydrating saccharide or oligosaccharide; providedthat at least one of R and R¹ is -L-S; or a pharmaceutically acceptablesalt thereof.
 2. The compound of claim 1, wherein R is hydrogen or—C(O)alkyl and R¹ is -L-S.
 3. The compound of claim 1, wherein R is -L-Sand R¹ is hydrogen.
 4. The compound of claim 1, wherein R and R¹ are-L-S.
 5. The compound of claim 1, wherein R is hydrogen, mannopyranose,glucopyranose, glucopyranose-O—(CH₂)₉C(O)—, ribofuranose, ribopyranoseor mannitol.
 6. The compound of claim 1, wherein R¹ is hydrogen,glucopyranose-O—(CH₂)₈C(O)—, —C(O)O(CH₂CH₂O)₃CH₃, —CO₂CH₂CH₃ ormannitol.
 7. The compound of claim 1, wherein the compound is selectedfrom the group consisting of


8. A pharmaceutical composition comprising a pharmaceutically acceptableexcipient and a therapeutically acceptable amount of a compound ofclaim
 1. 9. The pharmaceutical composition of claim 8, wherein R ishydrogen or —C(O)alkyl and R¹ is -L-S.
 10. The pharmaceuticalcomposition of claim 8, wherein R is -L-S and R¹ is hydrogen.
 11. Thepharmaceutical composition of claim 1, wherein both R and R¹ are -L-S.12. The pharmaceutical composition of claim 8, wherein thepharmaceutically acceptable excipient comprises mannitol.
 13. A methodfor treating pain in a patient which method comprises administering tosaid patient the pharmaceutical composition according to claim
 1. 14. Amethod for treating addiction in a patient which method comprisesadministering to said patient the pharmaceutical composition accordingto claim
 1. 15. A method for treating pain in a patient which methodcomprises administering to said patient a therapeutically effectiveamount of a compound of claim 1 or a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of claim 1and a pharmaceutically acceptable excipient.
 16. A method for treatingaddiction in a patient which method comprises administering to saidpatient a therapeutically effective amount of a compound of claim 1 or apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1 and a pharmaceutically acceptable excipient.